X-38408795-G-T

Variant names:

• chrX-38408795-G-T
• NM_000531.6:c.717G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_000531.6(OTC):​c.717G>T​(p.Glu239Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense, splice_region
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.75

Genes affected

OTC (HGNC:8512): (ornithine transcarbamylase) This nuclear gene encodes a mitochondrial matrix enzyme. The encoded protein is involved in the urea cycle which functions to detoxify ammonia into urea for excretion. Mutations in this enzyme lead to ornithine transcarbamylase deficiency, which causes hyperammonemia. [provided by RefSeq, May 2022]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-38408795-G-T is Pathogenic according to our data. Variant chrX-38408795-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664686.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.717G>T	p.Glu239Asp	missense_variant, splice_region_variant	Exon 7 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.717G>T	p.Glu239Asp	missense_variant, splice_region_variant	Exon 9 of 12		NP_001394021.1
OTC	XM_017029556.2	c.717G>T	p.Glu239Asp	missense_variant, splice_region_variant	Exon 7 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.717G>T	p.Glu239Asp	missense_variant, splice_region_variant	Exon 7 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-257326G>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000643344.1	n.*467G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 11			ENSP00000496606.1
OTC	ENST00000643344.1	n.*467G>T		3_prime_UTR_variant	Exon 8 of 11			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Dec 14, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The OTC c.717G>T variant is classified as PATHOGENIC (PM2, PP3, PS1_Moderate, PM1_Moderate, PP4_moderate) The OTC c.717G>T variant is a single nucleotide substitution that causes a glutamic acid to aspartic acid amino acid change at position 239 in the protein. This variant has not been reported in population databases, ClinVar or dbSNP (PM2). A deleterious effect is predicted (REVEL score 0.669), and SpliceAI prediction tools predict donor site loss (Δ0.86) (PP3). The same amino acid change has been reported in a patient with OTC deficiency (PMID16786505) and another patient has been reported with a different missense variant at the same amino acid residue also associated with OTC deficiency (PMID 28324312) (PS1_moderate). This variant is n a mutational hotspot (PM1_moderate). This individual is biochemically and clinically diagnosed with OTC deficiency, which is phenotype is entirely consistent with the OTC gene aetiology (PP4_moderate). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.67
Sift	Benign	0.084	T
Sift4G	Benign	0.14	T
Polyphen		0.18	B
Vest4		0.43
MutPred		0.84		Loss of phosphorylation at Y236 (P = 0.083);
MVP		1.0
MPC		0.52
ClinPred		0.57	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-38268048;